Effects of dietary supplementation in treatment and control of progression and complications of insulin-dependent diabetes mellitus: a systematic review with meta-analyses of randomized clinical trials

There is no safe and effective prevention for insulin-dependent diabetes (IDDM) mellitus, which makes it highly dependent on its treatment. This systematic review with meta-analyses of randomized clinical trials investigated the overall effects of dietary supplements of vitamins, minerals, trace elements, and non-essential compounds with antioxidant properties, fatty acids, and amino acids in IDDM. Searches of MEDLINE, Embase, CENTRAL, LILACS, The Grey Literature Report, and ClinicaTrials.gov, and citations from previous reviews were used to identify reports published through July 2023. The Risk of Bias 2 (RoB2) tool was used to analyze the risk of bias and GRADE was used to assess the quality of the results. Fifty-eight studies (n=3,044) were included in qualitative analyses and seventeen (n=723) in meta-analyses. Qualitative analyses showed few positive effects on some metabolic function markers, such as endothelial and renal function and lipid profile. Meta-analyses showed a positive effect of omega-3 on glycated hemoglobin (HbA1c) (RMD=-0.33; 95%CI: -0.53, -0.12, P=0.002; I2=0%; GRADE: low quality; 4 studies) and of vitamin D on fasting C-peptide (FCP) (RMD=0.05; 95%CI: 0.01, 0.9, P=0.023; I2=0%; GRADE: very low quality; 4 studies). Most studies showed bias concern or high risk of bias. A recommendation for dietary supplementation in IDDM cannot be made because of the few positive results within different interventions and markers, the serious risk of bias in the included studies, and the low quality of evidence from meta-analyses. The positive result of vitamin D on FCP is preliminary, requiring further investigation.

Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses.Provided in Methods Information sources 6 Specify all databases, registers, websites, organizations, reference lists and other sources searched or consulted to identify studies.Specify the date when each source was last searched or consulted.
Provided in Methods Search strategy 7 Present the full search strategies for all databases, registers and websites, including any filters and limits used.
Provided in Methods Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and

Provided in Methods
Effect measures 12 Specify for each outcome the effect measure(s) (e.g.risk ratio, mean difference) used in the synthesis or presentation of results. -

Synthesis methods 13a
Describe the processes used to decide which studies were eligible for each synthesis (e.g.tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).

Provided in Methods 13b
Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.

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13c Describe any methods used to tabulate or visually display results of individual studies and syntheses.

Provided in Methods 13d
Describe any methods used to synthesize results and provide a rationale for the choice(s).If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.

Provided in Methods 13e
Describe any methods used to explore possible causes of heterogeneity among study results (e.g.subgroup analysis, meta-regression).

Provided in Methods
13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results.Provided in Methods Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).

Provided in Methods
Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.

Study selection 16a
Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.Figure 1 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimates and its precision (e.g.confidence/credible interval), ideally using structured tables or plots.

Results
of syntheses 20a For each synthesis, briefly summarize the characteristics and risk of bias among contributing studies.

Completed in results 20b
Present results of all statistical syntheses conducted.If meta-analysis was done, present for each the summary estimate and its precision (e.g.confidence/credible interval) and measures of statistical heterogeneity.If comparing groups, describe the direction of the effect.

Figure S2 .
Figure S2.Risk of bias assessment using the tool Risk of Bias 2 (RoB2).D1: Domain 1 -Risk of bias arising from the randomization process; DS: Domain S -Risk of bias due to period and transition effects (only for crossover design studies); D2: Domain 2 -Risk of bias due to deviations from intended interventions (effect of assignment to intervention); D3: Domain 3 -Risk of bias due to missing outcome data; D4: Domain 4 -Risk of bias in measurement of the outcome; D5: Domain 5 -Risk of bias in selection of the reported result; OR: Overall rating; NA: Not applicable.*Main study; # Follow-up report of the main study.

Table S1 .
Strategies and terms to search for reports in the electronic databases.

Table S2 .
Characteristics of vitamin B complex, vitamin D, vitamin C, and vitamin E supplementation studies.

Table S3 .
Characteristic of the included mineral, trace elements, and antioxidant compounds supplementation studies.

Table S4 .
Characteristics of the included amino acid and fatty acid supplementation studies.